2 New Drugs Offer Options To Fight H.I.V. in Novel Ways

By LAWRENCE K. ALTMAN and ANDREW POLLACK

Published: February 28, 2007

Two new AIDS drugs, each of which works in a novel way, have proved safe and highly successful in large studies, a development that doctors said here on Tuesday would significantly expand treatment options for patients.

The two drugs, which could be approved for marketing later this year, would add two new classes of drugs to the four that are available to battle H.I.V., the AIDS virus. That would be especially important to tens of thousands of patients in the United States whose treatment is failing because their virus has become resistant to drugs already in use.

''This is really a remarkable development in the field,'' Dr. John W. Mellors of the University of Pittsburgh said at a news conference here at the 14th Annual Conference on Retroviruses and Opportunistic Infections.

Dr. Mellors, who was not involved in the studies but has been a consultant to the manufacturers of the drugs, said he ''wouldn't be going out on a limb'' to say the new results were as exciting as those from the mid-1990s, when researchers first discovered that cocktails of drugs could significantly prolong lives.

Dr. Scott Hammer, chief of infectious diseases at Columbia University Medical Center, who also was not involved in the studies but has been a consultant to the manufacturers, agreed that the new drugs ''will provide extended years of meaningful survival to patients.''

One drug, maraviroc, was developed by Pfizer, which has already applied for approval to sell it. The Food and Drug Administration has scheduled an advisory committee meeting on April 24 to discuss the application.

The other drug, raltegravir, was developed by Merck, which has said it will apply in the second quarter for approval.

Experts said the new drugs would be used in combination with older drugs. Both drugs stem from scientific findings made a decade or more ago that have peeled back the intricate molecular process used by H.I.V. to infect human immune system cells and to replicate themselves.

While there are now more than 20 approved drugs to treat H.I.V. and AIDS, there are only four different mechanisms by which the drugs work. In many patients, the virus develops resistance to one or more drugs, usually because patients do not take their drugs on time as prescribed.

And if the virus develops resistance to one drug in a class, it often becomes resistant to others in that class and sometimes in other classes. So AIDS experts have said there is an urgent need for drugs that work by new mechanisms.

The two new drugs would represent the first new classes since 2003, when an injectable drug called Fuzeon was approved. They would be the first new classes of oral H.I.V. drugs in a decade.

Merck's drug works by inhibiting the action of integrase, an enzyme produced by the virus that incorporates the virus's genetic material into the DNA of a patient's immune cell. Once incorporated, the viral DNA commandeers the cell to make more copies of the virus.

In two Merck studies involving a total of 700 patients, virus levels dropped to below 50 copies per milliliter of blood, an amount considered undetectable, in about 60 percent of patients who received raltegravir. That compared with about 35 percent of those who received a placebo.

The patients in the two Phase 3 trials, typically the last stage of testing before approval, were resistant to at least one drug in each of three classes of antiretroviral drugs. All the patients also received a combination of older drugs that their doctors deemed to be the most appropriate. The results reported here were after 16 weeks, in a study that is continuing so it is possible that longer-term side effects might yet arise.

Other integrase inhibitors, like one from Gilead Sciences, are also under development. Gilead's drug is 18 months to 2 years behind Merck's.

Pfizer's drug works by blocking a protein on human immune system cells that H.I.V. uses as a portal to enter and infect the cell. It would be the first drug that targets the human body rather than the virus.

The portal, known as CCR5, was discovered in 1996 by several groups of scientists, and there has been a race to develop drugs to block it.

In two Phase 3 studies sponsored by Pfizer involving 1,049 patients, more than 40 percent of patients who received maraviroc had undetectable levels of virus after 24 weeks of a 48-week study. That was about twice the rate of those who received placebo. As in the Merck trials, patients were resistant to three classes of drugs and were receiving an optimized combination of older drugs.

Some experts said they were a bit cautious about maraviroc, in part because it blocks a human protein instead of a viral one, with possible unknown long-term effects. One CCR5 inhibitor that was being developed by GlaxoSmithKline was dropped because it caused liver toxicity, and a second being developed by Schering-Plough appeared to possibly raise the risk of blood cancers.

But in Pfizer's study there was no increased incidence of cancers. In one study there was a higher rate of death among those who took the drug, but Pfizer said the deaths were not associated with the drug.

Experts are also encouraged that about 1 percent of Caucasians have a particular mutation in both copies of their CCR5 gene that knocks out its function. These people are resistant to H.I.V. infection and apparently live otherwise normal lives.

Yet another issue is that some viruses use a different entry portal called CXCR4. Before getting maraviroc, patients will have to be tested to see which portal their virus uses, which would make the drug an early example of ''personalized medicine'' tailored to the patient.

The test, which will probably take two weeks for results, was developed by Monogram Biosciences of South San Francisco, Calif. It is expected to cost as much as $1,000, or more.

About 85 percent of newly infected patients have a virus that uses CCR5 while only about half of highly drug-resistant viruses use that portal. There has been some concern that blocking CCR5 would encourage the development of viruses that use the alternative portal -- and those viruses seem to be associated with worse outcomes.

But that has not proven so far to be a big problem, according to Edward A. Berger of the National Institute of Allergy and Infectious Diseases, who played a key role in the discovery of the two portals.

Government, academic and industry experts said there was no reliable estimate of the number of people who would need one of the new drugs. But the number is declining as more and better AIDS drugs become available.

''The numbers are not what they used to be six years ago,'' said Norbert Bischofberger, executive vice president for research and development at Gilead, which makes some widely used AIDS drugs.

Both Merck and Pfizer say they are conducting studies testing their drugs for use as initial treatments. They would not say how much their drugs would cost.